Cancer Immunology and Immune suppression

Question 1

What is the evidence of an immune response to cancer?

Answer 1

immune suppression increases tumour incidence; inflammatory immune responses can also promote tumour incidence; presence of immune response associated with prognosis

Question 2

Give examples of inflammatory immune responses promoting tumour incidence?

Answer 2

H.pylori and stomach cancer; hep B and liver cancer; pancreatitis and pancreatic cancer

Question 3

What cytokines promote tumour clearance?

Answer 3

IFNy and IL-2

Question 4

How does advanced cancer perpetuate immune dysfunction?

Answer 4

cell heterogeneity; TCR dysfunction; desnity of antigen on the tumour cells may be lower than the threshold for recognition; host system may be too overwhlemed; defective APCs; MDSC

Question 5

How does cancer cause TCR dysfunction?

Answer 5

change in quality (phosphorylation); change in quantitty (proteolysis) due to tumour microenvironment

Question 6

Which cells is TCR dysfunction in cancer first seen in?

Answer 6

TILs then in PBMCs

Question 7

How does cancer overwhelm the immune system?

Answer 7

continuous shedding of tumour associated antigen may induce tolerance; local Th2 response is stimulated; T cells less IL2 responsive

Question 8

How do cancers cause defective APCs?

Answer 8

lack of MHC-I expression of B7; lack of costimulation- anergy ; VEGF immunsuppresses APCs

Question 9

What do monocytic MDSCs differentiate to in tumour sites?

Answer 9

tumour associated macrophages and inflammatory DCs

Question 10

What are the 2 types of MDSC?

Answer 10

monocytic type and polymorphonuclear type

Question 11

What attracts monocytic MDSCs to the tumour site?

Answer 11

chemokines CCL2 and CCL5 and grwoth factor CSF-1

Question 12

What controls the differentiation of TAMs?

Answer 12

HIF-1a increase and STAT3 decrease

Question 13

What can TAMs differentiate into

Answer 13

M1 and M2 types

Question 14

What is the effect of both M1 and M2-like TAMs?

Answer 14

suppression of T cells

Question 15

How do M1-like TAMs inhibit T cell function?

Answer 15

NO

Question 16

How do M2-like TAMs inhibit T cell function?

Answer 16

arginase 1

Question 17

What does the functional outcome of the MDSC depend on/

Answer 17

tumour microenviroment

Question 18

When are MDSCs formed?

Answer 18

in the context of cancer, normally become monocytes or PBMCs

Question 19

What factor in the cancer microenvironment helps stimulate formation of TAMs?

Answer 19

hypoxia and VEGF

Question 20

What are the features of tumour mediated immune evasion?

Answer 20

loss of expression of mutation of tumour antigens; loss of antigen processing and presentation-MHC-1; expression of immunosuppressive factors; activation of Tregs; expression of decoys- soluble circulating tumour antigens; clonal exhaustion; tolerane induced by continuous shedding of TAAs; expression of PD-L1; loss of Fas;; intrisinsic resistance to apoptosis

Question 21

What are the authors of the hallmarks of cancer?

Answer 21

Hanahan and Weinberg

Question 22

What are hte hallmarks of cancer?

Answer 22

sustained proliferative signalling; resisting cell death; evading growth suppressors; activating invasion and metastasis; enabling replicative immortality; inducing angiogenesis; avoiding immune destruction

Question 23

What is the effect of APCs producing IDO and arginase?

Answer 23

inhibits CD3 function on CTLs

Question 24

What is the effect of IL-10 and TGFb produced by APCs?

Answer 24

induces Tregs which inhibit CTLs

Question 25

What are hte major mechanisms by which CTLs kill target cells?

Answer 25

perforin/granzyme and Fas/FasL

Question 26

How does the tumour have intrinsic resistance to apoptosis?

Answer 26

upregulation of anti-apoptotic proteins Bcl2, survivin

Question 27

What factors barrier the activation; proliferation and survival of naive tumour specific T cells?

Answer 27

CTLA-4; Tregs; TGFb; IL-10; lack of TLR signals ; lack of yc cytokines

Question 28

What prevents the activated tumour specific T cell migrating to the tumour site?

Answer 28

lack of chemokine expression by tyumours; lack of chemokine receptors on T cells

Question 29

What inhibits the effector functions of tumour-specific T cells?

Answer 29

Tregs; PD-L1; TGFb; IL-10; IDO; arginase; iNOD; VEGF

Question 30

What suggests taht ovarian tumours may be amenable to immune attack?

Answer 30

high numbers of TILs associated with better prognosis; express tumour antigens e.g CA-125

Question 31

How do ovarian cacners suppress the immune repsonse?

Answer 31

high Tregs associated with increased resistance to chemo and decreased survival; icnreased expression of PDl1; lipids in ascites can suppress NK activation; TNFa production generates an autocrine tumour-promoting network

Question 32

What is found on the intracellular domain of PD-1?

Answer 32

ITSM and ITIMs

Question 33

What binds to ITSM on intracellular domain of PD-1?

Answer 33

SHP-2

Question 34

What happens when PD-1 is activated?

Answer 34

SHP2 is able to dephosphorylate proximal signalling kinases of the TCR

Question 35

Which cells express PD-1?

Answer 35

activated T and B cells; macropahges

Question 36

What scientists were invovled in checkpoint inhibition mAbs?

Answer 36

Allison- CTLA4 and Honjo- PD-1

Question 37

What does engagement of PD-1 result in?

Answer 37

T cell anergy

Question 38

What was the recent clinical success of anti-PD1?

Answer 38

complete of partial response to different types of cancer- melanoma; renal cell carcinoma

Question 39

What is the name for the anti-PD1?

Answer 39

nivolumab

Question 40

What represents a challenge in the anti-PD1 therapy?

Answer 40

there is no correlation between tumour PD-L1 expression and response to therapy- unknown why some patients respond and others don't

Question 41

What is the name for the anti-CTLA4?

Answer 41

ipilumumab

Question 42

What is nivolumab approved for?

Answer 42

melanoma and small cell lung cancer

Question 43

What is ipilimumab approved for?

Answer 43

advanced melanoma

Question 44

What is the efficacy of ipilumamab?

Answer 44

aroudn 4 months increase in overall survival

Question 45

What is the difference between anti-CTLA4 and anti-PD1/PDL1?

Answer 45

anti-CTLA4 has higher increase in overall suvival but there are higher toxicities